The Role of Pyruvate Dehydrogenase Kinase-4 (PDK4) in Bladder Cancer and Chemoresistance

Advanced bladder cancer (BCa) remains a major source of mortality, with poor treatment options. Cisplatin based chemotherapy is the standard treatment, however many patients are or become resistant. One potential cause of chemoresistance is the Warburg Effect, a metabolic switch to aerobic glycolysis that occurs in many cancers. Upregulation of the pyruvate dehydrogenase kinase family (PDK1-4) is associated with aerobic glycolysis and chemoresistance through inhibition of the pyruvate dehydrogenase complex (PDH). We have previously observed upregulation of PDK4 in high grade compared to low grade bladder cancers. We initiated this study to determine if inhibition of PDK4 could reduce tumor growth rates or sensitize BCa cells to cisplatin. Upregulation of PDK4 in malignant BCa cell lines as compared to benign transformed urothelial cells was confirmed using qPCR. Inhibition of PDK4 with dichloroacetate (DCA) resulted in increased PDH activity, reduced cell growth, and G0/G1 phase arrest in BCa cells. Similarly, siRNA knockdown of PDK4 inhibited BCa cell proliferation. Co-treatment of BCa cells with cisplatin and DCA did not increase caspase-3 activity but did enhance overall cell death in vitro. While daily treatment with 200mg/kg DCA alone did not reduce tumor volumes in a xenograft model, combination treatment with cisplatin resulted in dramatically reduced tumor volumes as compared to either DCA or cisplatin alone. This was attributed to substantial intra-tumoral necrosis. These findings indicate inhibition of PDK4 may potentiate cisplatin induced cell death and warrant further studies investigating the mechanism through which this occurs.

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